BEX1 is an RNA-dependent mediator of cardiomyopathy.
BEX1 is an RNA-dependent mediator of cardiomyopathy.
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DOI：
10.1038/s41467-017-02005-1
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发表时间：
2017-11-30
影响因子：
16.6
通讯作者：
Molkentin JD
中科院分区：
文献类型：
--
作者：
Accornero F;Schips TG;Petrosino JM;Gu SQ;Kanisicak O;van Berlo JH;Molkentin JD
mRNA剪接、加工和稳定性的调节越来越被认为是压力或疾病期间动态改变基因表达的关键控制点。对心力衰竭的这一过程知之甚少。在这里，我们表明，BEX 1是一个心脏衰竭诱导基因作为mRNA相关蛋白，增强心脏疾病促进基因的一个子集的表达。通过对疾病中BEX 1增加进行建模，心脏特异性BEX 1转基因小鼠在应激刺激下表现出更严重的心脏病，而Bex 1基因缺失的小鼠则受到保护，免受促进心力衰竭的损伤。蛋白质组学和相互作用筛选分析表明，BEX 1是一个大型核糖核蛋白加工复合物的一部分，参与调节心脏中促炎性mRNA的表达。具体而言，BEX1的诱导增强了通常在促炎基因中发现的含有富含AU元件的mRNA的稳定性和表达。因此，BEX1作为一种mRNA依赖性效应子，在心力衰竭期间增强病理促进基因表达。目前对心力衰竭过程中mRNA剪接、加工和稳定性的变化知之甚少，这些变化可以改变基因表达。在这里，作者表明BEX 1在心力衰竭期间被诱导，并且是核糖核蛋白复合物的一部分，增强促炎基因的表达和稳定性。
Regulation of mRNA splicing, processing and stability is increasingly recognized as a critical control point in dynamically altering gene expression during stress or disease. Very little is understood of this process in heart failure. Here, we show that BEX1 is a heart failure-induced gene functioning as an mRNA-associated protein that enhances expression of a subset of cardiac disease-promoting genes. Modeling the increase in BEX1 that occurs in disease, cardiac-specific BEX1 transgenic mice show worse cardiac disease with stress stimulation, whereas Bex1 gene-deleted mice are protected from heart failure-promoting insults. Proteomic and interactive screening assays show that BEX1 is part of a large ribonucleoprotein processing complex involved in regulating proinflammatory mRNA expression in the heart. Specifically, induction of BEX1 augments the stability and expression of AU-rich element containing mRNAs typically found within proinflammatory genes. Thus, BEX1 functions as an mRNA-dependent effector that augments pathology-promoting gene expression during heart failure. Little is known about the changes in mRNA splicing, processing and stability that can alter gene expression during heart failure. Here, the authors show that BEX1 is induced during heart failure and is part of a ribonucleoprotein complex enhancing the expression and stability of proinflammatory genes.
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